Process of preparing phytone

ABSTRACT

Phytone is prepared from citral or pseudo-ionone by conversion thereof into a C14-pseudo-acetal or 7,11-dimethyl-4,6,10dodecatriene-1,1-lower-dialkyoxy-3-one, reaction of this acetal with a methylmagnesium halide to a C15-pseudo-hydroxy-acetal, hydrolysis of the latter into the corresponding aldehyde which is condensed with acetone to the C18-pseudo-ketone, and catalystic hydrogenation of the latter.

O United States Patent [151 3,676,499 Redel et al. [451 July 11, 1972 [54] PROCESS OF PREPARING PHYTONE [72] Inventors: Joseph Redel, Antony; Jean Baptiste [56] References Cited Christian Boch, Neris Les Bains, both of UNITED STATES PATENTS France 2,957,027 10/1960 Beets et al ..260/593 R [73] Assignee: A.E.C. Societe de Chimie Organique et Biologigque, Commentry, France OTHER PUBLICATIONS 22 Filed; Oct 3 9 3 Chemical Abstracts Vol. 68 Subject Index January- June.

(1968) page 29378. 21 Appl. No.: 772,285

Primary Examiner-Daniel D. Horwitz Related U.S. Apphcation Data Anomey young & Thompson [63] Continuation-impart of Ser. No. 482,681, Aug. 26,

1965, abandoned. [57] ABSTRACT Phytone is prepared from citral or pseudo-ionone by conver- [30] Foreign Application Priority Data sion thereof into a C -pseudQ-acetaI or 7,1 i-dimethyl-4,6,l0-

dodecatriene-l,i-lower-dialkyoxy-3-one, reaction of this Sept. 3, 1964 France ..64986944 acetal with, a methylmagnesium halide to a cwpseudw hydroxy-acetal, hydrolysis of the latter into the corresponding [52] U.S. Cl. ..260/593 R, 260/594, 260/615, aldehyde which is condensed with acetone to the cwpseudw 260/601 ketone, and cataiystic hydrogenation of the latter. [5 l Int. Cl ..C07c 49/20, C07c 49/06 [58} Field of Search ..260/593 R 2 Claims, 2 Drawing Figures 0 Walnut-a PROCESS or PREPARING PHYTQNE I This application is a continuation-in-part of application Ser. No. 482,681 filed Aug. 26, 1965, now abandoned.

The present invention relates to the preparation of phytone (I), ketone having the empirical formula C H O and the structural formula illustrated in FIG. 1 of the accompanying drawing,

Phytone is of high interest since it constitutes an appreciated intermediary, inter alia, in the synthetic preparation of isophytol and vitamins E and l(,.

A number of processes are already known for the synthetic preparation of phytone.

These known processes have drawbacks in that they start with expensive and rare materials, require a great number of operating stages, give poor yields or suffer from two or more of these defects.

The object of the invention is to remedy these drawbacks. The invention provides for this purpose an improved process for preparing phytone either in starting with citral or an equivalent amount of lemongrass oil, or in starting with pseudo-ionone which are readily available and relatively inexpensive products.

This process affords an entirely new way to phytone through a series of new intermediate products.

FIG. 2 of the accompanying drawing illustrates the whole of the synthetic preparation of phytone (I) from citral (II) or pseudo-ionone Ill) according to the invention.

This synthetic preparation comprises the preliminary preparation of a C -pseudo-acetal (VI), R being a lower alkyl group and singularly methyl that is to say, of a 7,1l-dimethyl- 4,6,l-dodecatriene-l,l-lower dialkoxy-3-one.

The compounds (VI) are new. They are prepared from citral (II) by condensation of the latter according to stage (a) with an acetal of ,B-ketobutyraldehyde (IV). I

This condensation is advantageously effected in an anhydrous medium in the presence of an alkali metal alkoxide of a lower alkanol at a temperature between about 30 C and +1 0 C, preferably between about 20 C and -l0 C. A number of anhydrous organic solvents can be used as reaction medium, such as dialkyl ethers, hydrocarbons and chlorinated hydrocarbons.

To obtain the compounds (VI) from pseudo-ionone (III) which can be obtained in the conventional manner by condensation of citral (II) with acetone (stage a,), the pseudo-ionone is formylated according to Claisens method so as to obtain according to stage (a the enolate (V) which is directly acetalized (stage a into compound (VI).

More specifically, stages (a,'), (a and (a can be carried out as follows.

In stage (a,), an excess of acetone is used as solvent and the condensation with citral is effected in alkaline medium at a temperature between about 20 C and the reflux temperature of the reaction medium.

To formylate pseudo-ionone (stage a the latter is contacted with a lower alkanol formate in an anhydrous medium in the presence of an alkali metal alkoxide of a lower alkanol at a temperature between about 0 C and 30 C, preferably between about and 25 C. A number of anhydrous organic solvents can be used as reaction medium, such as hydrocarbons and dialkyl ethers.

The enolate (V) is acetalized (stage a by means of a lower alkanol in acidic medium at a temperature between about 0 C and C. The enolate (V) need not be isolated. As a matter of fact, it is sufficient to acidify the reaction medium obtained at the end of stage a by means of a strong and anhydrous inorganic acid, such as hydrochloric or sulfuric acid, and to add thereto the lower alkanol.

Although, both ways (a) and (a (a (with or without a,) can be equally used, way (a (a is preferred since it makes use of cheaper reactants and gives better yields.

After obtainment of the compound (VI) the succession of stages is the following stage (b. Action of organo-magnesium compound Cl-I MgX, X being a halogen, on the compound (VI) converting the latter into a C -pseudo-hydroxyacetal (VII) or 3,7,11- trimethyl 4,6,10-dodecatriene 1,1-lower dialkoxy-Z-ol. The C -pseudo-hydroxyacetals (VII) are new compounds.

The Grignard-type reaction leading to these compounds (VII) is conveniently carried out in an ether, as solvent, at a temperature between about -20 C and the reflux temperature of the solvent, preferably between about 0 C and 20 C.

stage c. Hydrolysis of the compound VII )'with a hydrohalic acid, in particular hydrochloric acid, in an acetonic medium, into C, -,-pseudo-a.ldehyde (VIII) or 3,7,ll trimethyl-2,4,6,l0 dodecatetraenel-al which is a new compound.

This hydrolysis is advantageously effected at a temperature between about 20 C and the reflux temperature of the reaction medium.

stage (d. Condensation of the compound (VIII) with acetone in an alkaline medium giving C -pseudo-ketone (IX) or 6,10,l4-trirnethyl-3,5,7,9,IJ-pentadecaene-Z-one which is a new compound.

To effect this condensation, the compound (VIII) need not be isolated. It is sufficient to alkalinize the acetonic reaction medium obtained at the end of stage (c) by means of a strong base to carry out the condensation, the useful temperature range being the same as in stage (c). Thus, for all practical purposes, stages c and d are merged into one stage.

stag'e (e. Catalytic hydrogenation of the compound (IX) in the presence of palladinized charcoal giving saturated C pseudo-ketone or phytone (X).

This hydrogenation may be efiected in any organic solvent which is inert towards hydrogen such as alkanols, saturated aliphatic hydrocarbons and the like. The optimal temperature range is from about 0 C to 30 C and the pressure may vary from atmospheric pressure 'to 1 atmosphere gauge.

It is clear from the foregoing that applicants process comprises only a limited number of simple stages, especially if it is noted that stages (a and (a on the one hand, and stages (c) and (d), on the other hand, can each be merged practically into one stage.

The invention also covers as new industrial products the compounds (VI), (VII), (VIII) and (IX).

It should be mentioned in this respect that the preparation of C -pseudo-aldehyde (VIII) and C -pseudo-ketone (IX) have been described by Barraclough et al. (J. Chem. S oc., I939, 1549) by condensation of citral with dimethylacroleine followed by crotonization in acetone.

However, the constants of this product are ditferent from those that the Applicants measured from the specimens of (VIII) and (IX) obtained by their process, in particular as concerns the ultraviolet absorption wave length. The Applicants obtained the preparation according to Barraclough and noticed that the catalytic hydrogenation of the alleged ketone (IX) does not give phytone (X) (verification carried out by chromatography).

The following table shows the comparative tests Products VIII and Derivatives Preparation VIII IX Catalytic hydrogenation of IX max.=338 my (alcohol) Semicarbazone a: M.P.=l58-60 C max.=335 m Semicarbazone b: M.P.=19l93 0 Process of the applicants Barraclough et al. (J. Chem. Soc. 1989 1549).

X max.=324 my...

Repeat of Barracloughs work effected Amax.=315 my Semicarbazone a: M.P.=17678 A max.=358 m X max. =326 m by the applicants.

Phytone(X) B.P.. =120. Semicarbazone M.P.=69.5- C.

(M.P.=70-70.5): Smith & Sprung-J. Amer.

Chem. Soc. 1943 651285.

.: A max.=358 m m. Not effected.

Complete absence of phytone checked by CIPV and thin layer chromatography.

EXAMPLE 1. 7,1l-dimethyl 4,6,ld0decatriene-l,l-dimethoxy-3-one or C -pseudo-aceta1 (VI).

(starting with citral by condensation with acetal of ,8- ketobutyraldehyde stage(a) 50 g of citral (1I)(or corresponding amount of lemongrass oil), 91 g of dimethylic acetal of B-ketobutyraldehyde (1V) (commercial product), 475 cc of anhydrous methylene chloride are placed in a three-necked flask and a solution of9 g of sodium methylate in 25 cc of absolute methyl alcohol are added slowly at 10 C. Stirring is continued for 1 hr 30 min. at l0 C. The product is extracted with ether, washed with water and then several times with a solution of dilute sodium hydroxide, once with 5 percent bicarbonate, and then with water until neutrality. The product is dried on sodium sulphate and concentrated under low pressure.

Weight 109 g Amax. 295 my. E 929 (isopropanol) Analysis: C H O M.W. 266.38

Theoretical 7c C 72.14 H 9.80 Found 72.05 9.94 71.99 9.76

2. 7,1l-dimethyl-4,6,10-dodecatriene-1,l-dimethoxy-3-one or C -pseudo-acetal (V1).

(starting with pseudo-ionone stages (a and (a 1 10 g of ethyl formate in solution in 140 cc of hexane are added in min at 19 C to a suspension of 60 g of sodium methoxide in 600 cc of hexane. As soon as the addition has been effected, the product is stirred for 30 min. and 150 g of pseudo-ionone (11) in solution in 300 cc of hexane are added and stirring is continued for 3 hr. 30 min. The enolate thus prepared is added at 0 C to a solution of 75 cc of sulphuric acid in 900 cc of anhydrous methanol. After stirring for 2 hr., the product is poured onto an aqueous solution of iced bicarbonate and extracted with hexane.

Weight 203 g Amax. 295 mp.- E 847 (isopropanol) 3. 3,7,1l-trimethyl-4,6,l0-dodecatriene-l,1-dimethoxy-3- 01 or C -pseudo-hydroxy-acetal (V11) stage b There is added at 0 C to an organomagnesium compound prepared in the usual manner from 4.88 g of magnesium in 200 cc of anhydrous tetrahydrofuran (or diethyl ether), within 1 hr. a solution of 40 g of C -pseudo-acetal (V1) in 40 cc of tetrahydrofuran. Stirring is continued for 2 hr. at room temperature. The product is decomposed with a 5 percent hydrochloric acid solution and extracted with ether, dried and concentrated under low pressure.

Weight 42 g BR, 140 C Amax. 240 mp. E 925 (isopropanol) Analysis: C H M.W. 282.44

Theoretical C 72.29 H 10.70 Found 72.38 10.55 72.39 10.75

4. 3,7,11trimcthy1-2,4,6,l0-dodecatetraenc-1-al or C pscudo-aldchydc (V111) stage c 5 g of C -pseudo-hydroxy-acetal (V11) are put in solution in 37.5 cc of acetone. The solution is heated under reflux and 2 cc of N hydrochloric acid are added.

After 45 min., the absorption maximum has moved to 338 mg. The product is poured into a cooled 5 percent sodium bicarbonate solution and extracted with ether.

Weight= 3.85 g

hmax. 338 mu E 1045 (ethanol) Amax. 338 mp.- E 1082 (isopropanol) Semicarbazone. The semicarbazones a and b are isolated from the mixture of the stereoisomer semicarbazones obtained in the usual manner.

Semicarbazone a M.P. 158160 C (crystallized in methanol) Amax. 335 m,u E 2365 (isopropanol) Analysis: C H ON M.W.=275.40

Theoretical C 69.78 H 9.15 Found 69.89 9.17 70.05 9.36

Semicarbazone b M.P. l91l 93 C (crystallized in methanol) Amax. 335 mp. 15 2490 (isopropanol) Amax. 335 m,u. E 2500 (ethanol) Analysis: C H ON M.W. 275.40

Theoretical C 69.78 H 9.15 Found 69.91 9.47 69.73 9.04

5. 6,l0,l4-trimethy1-3,5,7,9,13-pentadeca-pentaene-Z-one or C -pseudo-ketone (1X) stage d The C -pseudo-aldehyde (VIII) is prepared, as described in the preceding example, from g of C, -pseudo-hydroxyacetal, 750 cc of acetone and 40 cc of N hydrochloric acid.

After refluxing for 25 min., the mixture is cooled and 245 cc of N sodium hydroxide are added. Stirring is continued for 1 hr. at room temperature, the absorption being then 370 mu The product is poured into water, neutralized with dilute hydrochloric acid and extracted with ether.

Weight 89 g Amax. 368 my. E 1088 (isopropanol) 6. 6,10,14-trimethyl-Lpentadecanone or saturated C pseudo-ketone or phytone (l) stage 2 128.5 g ofC -pseudo-ketone (1X) are put in solution at 95 C in 640 cc of ethyl alcohol. 6.42 g of 5 percent palladium on charcoal and hydrogen are added at room temperature under a pressure of 50 cm of water until the absorption of hydrogen stops.

The product is filtered on sintered glass and concentrated. Weight 125 g BP. C n 1.448 Semicarbazone (White flakes in methanol).

M.P. 69.5-70 C (Smith and Sprung, J.Amer.

Chem. Soc.1943 65 1285 indicate MP 7070.5 C).

CIQHNONH Theoretical N 12.90 Found Analysis: M.W. 325.54

a. conversion of pseudo-ionone into c -pseudo-acetalz 7,1l-dimethyln4,6,10-dodecatriene- 1, l-lower dialkoxy-3- one by formylation of pseudo-ionone followed by the acetalization of the enolate obtained as a result of this formylation, said formylation being effected at a temperature between about C and 30 C in an anhydrous medium by means of a lower alkanol formate in the presence of an alkali alkoxide of a lower alkanol and said acetalization being effected by acidifying, with a strong and anhydrous inorganic acid, the reaction medium of the formylation step and adding thereto a lower alkanol;

. treatment of the C -pseudo-acetal with the organomagnesium compound CH MgX, X being a halogen, in an ether at a temperature between about 20 C and the reflux temperature, converting it into C, -pseudo-hydrox- 2.6,l0,l4-trimethyl-3,5,7,9,l3-pentadecaene-2-one.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No- 3,676,499 a e o July Ii LlQ72 Inventor(s) JOSph Re del et. a1.

It is certified that error appears in theabove-identified patent and that said Letters Patent are hereby corrected as shown below:

On the cover sheet taol, "64986944" should read 986994 Signed end sealed this 15th day of May 1973.

(SEAL) Attes't:

EDWARD M.FLETCHER,JR.

ROBERT GOTTSCHALK Attesting Officer 9 Commissioner of Patents FORM PO-l050 (10-69) USCOMM-DC 6O376-P69 u.s4 GOVERNMENT PRINTING OFFICE I969 o-sss-asa, 

2. 6,10,14-trimethyl-3,5,7,9,13-pentadecaene-2-one. 